JP5951920B1 - New aqueous composition - Google Patents

Abstract

Providing a technique for suppressing crystal precipitation of a halogenated isoquinoline derivative-containing aqueous composition during low-temperature storage. The following general formula (1) [wherein X represents a halogen atom. Or a salt thereof or a solvate thereof, and brimonidine or a salt thereof.

Description

  The present invention relates to an aqueous composition and the like.

  The following structural formula:

Ripasudil (chemical name: 4-fluoro-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline) and the following structural formula:

Halogenated isoquinoline derivatives such as 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline represented by the formula: For example, it has patent documents 1 and 2) and is known to be useful for prevention and treatment of eye diseases. Specifically, for example, it has been reported that it is suitable for the prevention or treatment of ocular hypertension and glaucoma (for example, Patent Document 3) in which it is useful to lower intraocular pressure.

  Therefore, it is extremely useful to establish a technique for stably formulating these halogenated isoquinoline derivatives as, for example, ophthalmic agents.

Japanese Patent No. 4212149 International Publication No. 2006/115244 Pamphlet International Publication No. 2006/068208 Pamphlet

The ophthalmic agent is usually a composition containing water (aqueous composition). The present inventor prepared an aqueous composition containing Ripasudil when formulating Ripasudil which is a halogenated isoquinoline derivative as an ophthalmic agent and the like, and confirmed its storage stability. It has been found that the problem of precipitation occurs.
Therefore, an object of the present invention is to provide a technique for suppressing crystal precipitation of a halogenated isoquinoline derivative-containing aqueous composition during low-temperature storage.

  Therefore, the present inventor has intensively studied to solve the above problems, and by adding brimonidine or a salt thereof to an aqueous composition containing a halogenated isoquinoline derivative such as ripaspil, crystal precipitation during low-temperature storage can be achieved. The present invention has been completed by finding that it can be suppressed.

  That is, the present invention provides the following general formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof, and brimonidine or a salt thereof.
The present invention also provides a crystal of an aqueous composition comprising a step of allowing brimonidine or a salt thereof to be contained in an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof. A method for suppressing precipitation is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the crystal | crystallization precipitation at the time of low temperature preservation | save of the aqueous composition containing halogenated isoquinoline derivatives, such as a ripaspil, can be suppressed.

Although this specification is not limited to these at all, the invention of the following aspects is disclosed, for example.
[1] The following general formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof, and brimonidine or a salt thereof.
[2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is ripaspil.
[3] The aqueous composition according to [1], wherein the compound represented by the general formula (1) or a salt thereof or a solvate thereof is ripaspil hydrochloride.
[4] The aqueous composition according to any one of [1] to [3], wherein brimonidine or a salt thereof is brimonidine tartrate.
[5] The aqueous composition according to any one of [1] to [4], which is an ophthalmic agent.
[6] The aqueous composition according to any one of [1] to [4], which is an eye drop.
[7] The aqueous composition according to any one of [1] to [6], which is an agent for preventing and / or treating ocular hypertension and / or glaucoma.

[8] Furthermore, α1 receptor blocker, α2 receptor agonist, β blocker, carbonic acid dehydrogenase inhibitor, prostaglandins, sympathomimetic agent, parasympathomimetic agent, calcium antagonist and cholinesterase inhibitor The aqueous composition according to any one of [1] to [7], which contains one or more selected from the group consisting of:
[9] Furthermore, it contains at least one member selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, nipradilol, timolol, bunazosin, dorzolamide, brinzolamide and isopropyl unoprostone, and salts thereof. 7] The aqueous composition according to any one of [7].

[10] Inhibition of crystal precipitation of an aqueous composition, comprising a step of allowing brimonidine or a salt thereof to be contained in an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof. Method.
[11] The method according to [10], wherein the compound represented by the general formula (1) is ripaspil.
[12] The method according to [10], wherein the compound represented by the general formula (1) or a salt thereof or a solvate thereof is ripaspil hydrochloride.
[13] The method according to any one of [10] to [12], wherein brimonidine or a salt thereof is brimonidine tartrate.
[14] The method according to any one of [10] to [12], wherein the aqueous composition is an ophthalmic agent.
[15] The method according to any one of [10] to [12], wherein the aqueous composition is an eye drop.
[16] The method according to any one of [10] to [15], wherein the aqueous composition is a preventive and / or therapeutic agent for ocular hypertension and / or glaucoma.

[17] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonic acid dehydrogenase inhibitor, a prostaglandin, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist. The method in any one of [10]-[16] containing 1 or more types chosen from the group which consists of an agent and a cholinesterase inhibitor.
[18] The aqueous composition further contains one or more selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, nipradilol, timolol, bunazosin, dorzolamide, brinzolamide and isopropylunoprostone, and salts thereof. [10] The method according to any one of [17].

In the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. In the general formula (1), the halogen atom is preferably a fluorine atom or a bromine atom, particularly preferably a fluorine atom.
In the general formula (1), the carbon atom constituting the homopiperazine ring substituted with a methyl group is an asymmetric carbon. Therefore, although stereoisomerism occurs, the compound represented by the general formula (1) includes any stereoisomer, and may be a single stereoisomer or a mixture of various stereoisomers in any ratio. . As a compound represented by the said General formula (1), the compound whose absolute configuration is S configuration is preferable.

The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, Inorganic acid salts such as hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate And organic acid salts such as toluene sulfonate, naphthalene sulfonate, camphor-sulfonate, and the like, and hydrochloride is preferable.
Further, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcohol solvate, and is preferably a hydrate.

  Specific examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include lipasyl (chemical name: 4-fluoro-5-{[(2S) -2-methyl- 1,4-diazepan-1-yl] sulfonyl} isoquinoline) or a salt thereof or a solvate thereof; 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] Sulfonyl} isoquinoline or a salt thereof, or a solvate thereof.

  Examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include Ripasudil or a salt thereof or a solvate thereof, 4-bromo-5-{[(2S) -2-methyl- 1,4-diazepan-1-yl] sulfonyl} isoquinoline or a salt thereof or a solvate thereof is preferable, ripaspil or a salt thereof or a solvate thereof is more preferable, and ripaspil or a hydrochloride thereof or a hydrate thereof. Is more preferred and has the following structural formula:

Ripasudil hydrochloride hydrate represented by the formula (Ripazil monohydrochloride dihydrate) is particularly preferred.

  The compound represented by the general formula (1) or a salt thereof or a solvate thereof is known and can be produced by a known method. Specifically, for example, Ripasudil or a salt thereof or a solvate thereof can be produced by a method described in International Publication No. 1999/020620 Pamphlet, International Publication No. 2006/057397 Pamphlet or the like. Further, 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline or a salt thereof or a solvate thereof is disclosed in International Publication No. 2006/115244 pamphlet. It can be produced by the method described.

  The content of the compound represented by the general formula (1) or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and is appropriately determined according to the disease applied, the sex, age, symptoms, etc. of the patient. However, from the viewpoint of obtaining an excellent pharmacological action, 0.01 to 10 w / v in terms of the free form of the compound represented by the general formula (1) with respect to the total volume of the aqueous composition. %, Preferably 0.02 to 8 w / v%, more preferably 0.04 to 6 w / v%. Among them, in the case of using ripaspil as the compound represented by the general formula (1), from the viewpoint of obtaining an excellent pharmacological action, ripaspil or a salt thereof or a solvate thereof is used with respect to the total volume of the aqueous composition. It is preferably contained in a free form in an amount of 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.15 to 2 w / v%.

As used herein, “brimonidine or a salt thereof” includes not only brimonidine but also a pharmaceutically acceptable salt of brimonidine. These are known compounds. For example, they can be produced by a known method described in US Pat. No. 3,890,319 or the like, and commercially available products can be used.
Specific examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride and hydrobromide; acetate, tartrate, lactate, citric acid, and the like. Acid salts, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, etc. Among them, tartrate is preferable. In the present invention, brimonidine or a salt thereof includes brimonidine, brimonidine tartrate (brimonidine monotartrate) (chemical name: 5-Bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6 -amine mono- (2R, 3R) -tartrate) is preferred.

The content of brimonidine or a salt thereof in the aqueous composition is not particularly limited, but from the viewpoint of the crystal precipitation suppression effect, in addition to the intraocular pressure lowering action of brimonidine or a salt thereof, the total volume of the aqueous composition is increased. On the other hand, it is preferably contained in an amount of 0.01-1 w / v% in terms of brimonidine free form, more preferably 0.02-0.5 w / v%, more preferably 0.03-0.1 w / v. % Content is particularly preferable.
In addition, the content mass ratio of the compound represented by the general formula (1) or the salt thereof or the solvate thereof and brimonidine or the salt thereof in the aqueous composition is not particularly limited. It is preferable to contain 0.01 to 1.5 parts by mass of brimonidine or a salt thereof in terms of the free form of brimonidine, based on 1 part by weight of the compound represented by the general formula (1). 0.04-0.8 parts by mass is more preferable, and 0.08-0.3 parts by mass is particularly preferable. In particular, in the case where the compound represented by the general formula (1) or a salt thereof or a solvate thereof is Ripasudil or a salt thereof or a solvate thereof, Lipasudil free It is preferable to contain 0.02 to 1 part by mass of brimonidine or a salt thereof in terms of a free body of brimonidine, and 0.06 to 0.5 parts by mass in terms of 1 part by mass in terms of body. More preferably, 0.1 to 0.2 parts by mass is particularly preferable.

The aqueous composition containing the compound represented by the general formula (1) typified by Ripasudil or a salt thereof or a solvate thereof can be a problem of crystal precipitation during low-temperature storage. As disclosed in the above, it has been clarified that by adding brimonidine or a salt thereof to the aqueous composition, crystal precipitation during low-temperature storage is suppressed as compared with the case where no brimonidine or a salt thereof is contained. Therefore, the compound represented by the general formula (1) or a salt thereof, or a solvate thereof, and an aqueous composition containing brimonidine or a salt thereof have suppressed crystal precipitation during low-temperature storage, and thus are stable in storage. It has the merit that it is excellent in property.
In addition, the intraocular pressure lowering action of the compound represented by the general formula (1) typified by Ripasudil or a salt thereof or a solvate thereof and brimonidine or a salt thereof is combined to show a further excellent intraocular pressure lowering action. Is extremely useful for ocular hypertension and glaucoma, but it can be combined into one preparation without using these multiple components in combination, and it is also excellent from the viewpoint of suppressing therapeutic compliance decline. Have the benefits.

In the present specification, the “aqueous composition” means a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment), and liquid is preferred. . In addition, as water in a composition, purified water, water for injection, sterilized purified water, etc. can be used, for example.
Although content of the water contained in an aqueous composition is not specifically limited, 5 mass% or more is preferable, 20 mass% or more is more preferable, 50 mass% or more is further more preferable, 90 mass% or more is further more preferable, 90- 99.8% by mass is particularly preferred.

  The aqueous composition can be made into various dosage forms according to a known method described in, for example, the 16th revised Japanese Pharmacopoeia General Rules for Preparations. Examples of the dosage form include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal solutions, enemas, external liquids, sprays, ointments, gels, oral solutions, syrups, etc. Is mentioned. As the dosage form, from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1), ophthalmic agents, specifically eye drops and eye ointments are preferable, and eye drops are particularly preferable.

In addition to the above, the aqueous composition may contain additives that are used in medicines, quasi drugs, etc., depending on the dosage form. Such additives include, for example, inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspensions. Examples include turbidizers, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, and the like.
Specific examples of such additives include ascorbic acid, potassium aspartate, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, ethylene / vinyl acetate copolymer. , Sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorhexidine gluconate solution, Lolobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, sodium hydroxide , Polyoxyl stearate 45, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed Tocopherol, white petrolatum, mint water, mint oil, concentrated benzalkonium chloride solution 50, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, Palau Methyl benzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, glacial acetic acid, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium Chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200) polyoxypropylene glycol (70), polystyrene sulfonate sodium, polysorbate 80, polyoxyethylene Hardened castor oil 60, polyvinyl alcohol (partially saponified product), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous citrus Acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, Examples include oxyquinoline sulfate, liquid paraffin, camphor, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, petrolatum, etc. The

  Examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate. , Concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified product), macrogol 4000, macro Goal 6000, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methyl cellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate Potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, l-menthol is preferable.

  In addition to the above, the aqueous composition may further contain other medicinal ingredients depending on the disease to be applied. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin such as bunazosin hydrochloride or a salt thereof or a solvate thereof; α2 receptor operation including apraclonidine or a salt thereof or a solvate thereof. Medicine: Carteolol such as carteolol hydrochloride or a salt thereof or a solvate thereof, nipradilol or a salt thereof or a solvate thereof, timolol or a salt thereof such as timolol maleate or a solvate thereof, betaxolol hydrochloride Betaxolol or a salt thereof such as a salt or a solvate thereof, Levobunolol or a salt thereof such as levobanolol hydrochloride or a solvate thereof, befnolol or a salt thereof or a solvate thereof, metipranolol or a salt thereof or the like Β-blockers including solvates; Dorzolamide or a salt thereof such as zolamide hydrochloride or a solvate thereof, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorofenamide or a salt thereof or a solvate thereof , Metazolamide or a salt thereof or a solvate thereof, carbonic acid dehydrogenase inhibitor; isopropyl unoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate thereof, travoprost or a salt thereof Prostaglandins including salts or solvates thereof, bimatoprost or a salt thereof or solvates thereof, latanoprost or a salt thereof or solvates thereof; dipivefrin such as dipivefrin hydrochloride or the like Salts or solvates thereof, epinephrine Sympathomimetic drugs including epinephrine or salts thereof such as epinephrine borate, epinephrine hydrochloride or solvates thereof; distigmine bromide or salts thereof or solvates thereof, pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, etc. Pilocarpine or a salt thereof, or a solvate thereof, carbachol or a salt thereof, or a parasympathomimetic agent comprising a solvate thereof; a lomeridine or a salt thereof such as romeridine hydrochloride or a calcium antagonist comprising a solvate thereof; Deme potassium or a salt thereof or a solvate thereof, an ecothiophosphate or a salt thereof or a solvate thereof, a cholinesterase inhibitor containing physostigmine or a salt thereof or a solvate thereof, and the like, one or two of these More than seeds Yes.

  As other medicinal ingredients, one or more selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, nipradilol, timolol, bunazosin, dorzolamide, brinzolamide and isopropyl unoprostone, salts thereof and solvates thereof are included. Preferably, at least one selected from the group consisting of nipradilol, timolol, bunazosin, dorzolamide, brinzolamide and isopropyl unoprostone, salts thereof and solvates thereof is more preferable.

  Although pH of an aqueous composition is not specifically limited, 4-9 are preferable, 4.5-8 are more preferable, and 5-7 are especially preferable. Moreover, although the osmotic pressure ratio with respect to the physiological saline is not particularly limited, 0.6 to 3 is preferable, and 0.6 to 2 is particularly preferable.

The aqueous composition is preferably contained in a container from the viewpoint of storage stability, portability, and the like. The form of the container is not particularly limited as long as the aqueous composition can be accommodated, and may be appropriately selected and set according to the dosage form and the like. Specific examples of such a container include, for example, an injection container, an inhaler container, a spray container, a bottle container, a tube container, an eye drop container, a nasal drop container, Examples include ear container, bag container and the like. Moreover, these containers may be further packaged by boxes, bags or the like.
The material (material) of a container is not specifically limited, What is necessary is just to select suitably according to the form of a container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal and the like. From the viewpoint of workability, squeeze property and durability, it is preferably made of plastic. The resin of the plastic container is preferably a thermoplastic resin. For example, polyolefin resins such as low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, polypropylene, and cyclic polyolefin. Polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly (1,4-cyclohexylenedimethylene terephthalate), polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamides Resin, polyvinyl chloride resin, styrene resin and the like, and a mixture thereof (polymer alloy) may be used.

The disease to which the aqueous composition is applied is not particularly limited, and may be appropriately selected depending on the pharmacological action and the like of the compound represented by the general formula (1).
Specifically, for example, it can be used as a prophylactic or therapeutic agent for ocular hypertension and glaucoma based on the Rho kinase inhibitory action and intraocular pressure-reducing action of the compound represented by the general formula (1). Here, as glaucoma, more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous production glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma Steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like.
When the aqueous composition of the present invention is used as an agent for eye diseases, it may be applied once or twice a day, and preferably twice a day.

Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.
In the following test examples, Ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in International Publication No. 2006/057397. Brimonidine tartrate can be produced, for example, by the method described in US Pat. No. 3,890,319.

[Test Example 1] Preservation test An aqueous composition having the formulation shown in Table 1 was prepared by a conventional method, and stored at -5 [deg.] C., and periodically evaluated for the presence or absence of crystal precipitation. First, it was confirmed whether crystal precipitation was observed. The results are shown in Table 1, where ○ indicates that no crystal precipitation was first observed, and x indicates that crystal precipitation was previously observed.

As shown in Table 1, it is clear that when the brimonidine tartrate is further added to the aqueous composition containing ripaspil, crystal precipitation during low-temperature storage is suppressed as compared with the case where no brimonidine tartrate is contained. It became.
From the above test results, when brimonidine or a salt thereof is further added to an aqueous composition containing the compound represented by the general formula (1) typified by Ripasudil or a salt thereof or a solvate thereof, it is stored at a low temperature. As a result, it became clear that crystals were relatively difficult to precipitate and that the storage stability was excellent.

[Production Examples 1 to 27]
An aqueous composition containing the components and amounts shown in Tables 2 to 4 (amount (g) per 100 mL of the aqueous composition) can be produced by a conventional method.

[Production Examples 28-54]
In Production Examples 1 to 27, the same amount of 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline was used instead of ripaspil monohydrochloride dihydrate. Can be produced as an aqueous composition of Production Examples 28 to 54 by a conventional method.

  ADVANTAGE OF THE INVENTION According to this invention, the aqueous composition excellent in storage stability can be provided and it can utilize suitably in pharmaceutical industry etc.

Claims (7)

The following general formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof, and brimonidine or a salt thereof.   The aqueous composition according to claim 1, wherein the compound represented by the general formula (1) is ripaspil.   The aqueous composition according to claim 1, wherein the compound represented by the general formula (1) or a salt thereof or a solvate thereof is ripaspil hydrochloride.   The aqueous composition according to any one of claims 1 to 3, wherein brimonidine or a salt thereof is brimonidine tartrate.   The aqueous composition according to any one of claims 1 to 4, which is an ophthalmic agent.   It is an eye drop, The aqueous composition in any one of Claims 1-4.   The aqueous composition according to any one of claims 1 to 6, which is used for prevention and / or treatment of ocular hypertension and / or glaucoma.